The pH perspective of cancer: From warburg's misconception to therapeutic targeting of pH regulating proteins.

The acidification of the tumor microenvironment is a hallmark of malignant tumors, resulting from the coordinated action of multiple pH-regulating proteins.pH-regulating Key molecules, including the sodium-hydrogen exchanger (NHE), bicarbonate transporters, monocarboxylate transporters (MCTs), V-type ATPase (V-ATPase), and carbonic anhydrases (CAs) play central roles in tumor metabolic reprogramming and microenvironmental acidification. This review re-examines the Warburg effect and proposes that cytoplasmic alkalinization is the critical switch that initiates aerobic glycolysis and inhibits oxidative phosphorylation. The review further analyzes the roles of pH-regulating proteins in tumor migration, invasion, and therapeutic resistance, and summarizes therapeutic strategies targeting these proteins. Finally, the review outlines future directions for multi-target synergistic interventions and clinical translation, thereby providing a theoretical foundation for developing novel precision therapies that target tumor pH regulation.